The present invention relates generally to methods for the synthesis of optically pure 4-aryl-2-hydroxytetronic acid aci-reductone compounds.
The aci-reductone 4-(4-chlorophenyl)-2-hydroxytetronic acid compound (CHTA) possesses antilipidemic and antiaggregatory properties which differ from those of the classical phenoxyactetic acids as has been disclosed in Witiak et al. J. Med. Chem., 1988, 31:1434-1445 and Kamanna et al., Lipids, 1989, 24:25-32. Although unsubstituted-, 2-alkyl- and 2-acyltetronic acids are frequently found in nature, the 2-hydroxy substituted redox system is found only in vitamin C and its closely related relatives (isoascrobic acid, erythroascorbic acid) and derivatives, and the macrolide antibiotic chlorothricin.
The antiaggregatory activities of 2-hydroxytetronic acid aci-reductone compound (CHTA) is of interest since blood platelets are involved in the genesis of atherosclerosis. 2-Hydroxytetronic acid aci-reductones inhibit collagen-induced human platelet aggregation and secretion of .sup.14 C!-serotonin in a concentration-dependent manner at equivalent doses, as reported in Witiak et al., J. Med. Chem., 1982, 25:90-93. The CHTA compound inhibits platelet function by a similar mechanism, involving arachidonic acid release. Redox analogues, such as 2-hydroxytetronic acid, function as antioxidants in membranes or interfere with free radical processes involved in the biosynthetic elaboration of cyclic prostaglandin endoperoxides (PGG.sub.2 and PGH.sub.2), and, subsequently, thromboxane A.sub.2 from arachidonic acid.
The synthesis of 4-aryl-2-hydroxytetronic acid compounds of the present invention is complicated by the stereochemical lability of the C-4 stereogenic center. The lability of this center in tetronic acids can be compared to the lability of the asymmetric center of mandelic acid; Whitesell et al., J. Org. Chem., 1983, 48:3548-3551 and Gore et al., J. Org. Chem., 1986, 51:3700-3704, and phenylglycine, Evans et al., Tetrahedron, 1988, 44:5525-5540, Bodansky, Principles of Peptide Syn., Springer-Verlag, Berlin, N.Y., 1984, p. 160, which discloses that phenylglycine undergoes extensive racemization during peptide synthesis.
Older synthetic methods such as disclosed in Helferich et al., Ber., 1937, 70:465-468, involving benzoin and intermolecular Claisen condensations employed in the synthesis of L-ascorbic acid, produce racemic 4-aryl-2-hydroxytetronic acids. Various syntheses published for the naturally occurring chiral tetronic acids such as (-)-vertinolide (Wrobel et al., J. Org. Chem., 1983, 48:3761-3764); (S)-carlosic acid (Bloomer et al., J. Org. Chem., 1974, 39:113-125); chlorothricin (Ireland et al., J. Org. Chem., 1986, 51:635-648); related 2-acylated (Booth et al., J.Chem. Soc. Perkin Trans I, 1987, 121-129; or 2-unsubstituted (Brandange et al., J. Org. Chem., 1984, 49, 927-928) tetronic acids, and chiral tetronic acid intermediates useful for the synthesis of the seco acid of erthronolide B (Stork et al., J. Am. Chem. Soc., 987, 109:1564-1565), were not applicable for the synthesis of optically pure enantiometers of 4-aryl-2-hydroxytetronic acids. Some targets contain quaternary chiral centers not expected to undergo racemization during their preparation as disclosed in Wrobel et al., supra, and Ireland et al., supra.
Syntheses for 2-hydroxytetronic acids other than ascorbic acid have been reviewed by Haynes and Plimmer in "Tetronic Acids," Quart, Rev., pp. 292-315 (1960), and by Shank, "Reductones," Synthesis pp 176-90 (1972) , 2-Hydroxytetronic acids have generally been prepared using three different routes: (1) hydroxyl group insertion at the 2 position of the corresponding tetronic acid nucleus; (2) intramolecular Claisen cyclization of substituted glyoxylate esters; and (3) base-promoted cyclization of 2,4-dihydroxy-3-ketobutanoates.
Witiak and Tehim, J. Org. Chem., 52.:2324-2327 (1987) have synthesized the 5- and 6-membered spiro 2-hydroxytetronic acids using propargyl alcohol conversion to methyl tetronate by treatment with sodium methoxide. Attempted hydroxylation at the 2-position by .alpha.-lithiation and reaction with dibenzoylperoxide provided only a 6% yield of the corresponding 2-benzoyloxytetronic acid. However, the 2-hydroxyl group was introduced in good yields by lithiation using lithium diisopropylamide (LDA), boronate ester formation B(MeO).sub.3 ! and oxidative hydrolysis (AcOH, H.sub.2 O.sub.2). Methyl 2-hydroxytetronate was converted to the corresponding aci-reductone by stirring in 48% HBr at 45.degree. C. for 12 hours. Ireland and Thompson, J. Org. Chem., 44:3041-3052 (1979), have utilized the Claisen condensation for construction of 2-hydroxytetronic acids.
Witiak and Tehim, J. Org. Chem., 52:2324-2327 (1987) have also prepared 5- and 6-membered spiro-2-hydroxytetronic acids using strategies developed by Ireland and Thompson, supra. This method was superior to use of hydroxyl group insertion methods because fewer steps were necessary and overall yields were higher. For example, Claisen cyclization of easily prepared methoxy or benzyloxy thiocarboxylate intermediates using LDA or lithium hexamethyldisilazide (LiHMDA) at -78.degree. C. occurred in high yields. The resultant 2-methoxytetronic acids underwent deprotection by acetylation and subsequent reaction with BBr.sub.3, whereas the 2-benzyloxytetronic acids were convertible to target 2-hydroxytetronic acid by transfer hydrogenation.
Witiak and Tehim, J. Org. Chem., 55:1112-1114 (1990), developed the first synthesis for optically pure (S)-(+)-4-phenyl-2-hydroxytetronic acid using the Claisen cyclization under kinetically controlled conditions. The 2-benzyloxyacetate derivative of the corresponding methyl mandelate underwent such cyclization at -100.degree. C. using the sterically hindered non-nucleophilic base, lithium dicyclohexylamide (LiDCyA). Subsequent benzyl group deprotection of the tetronic acid generated the desired compound in low overall yields; 12% for both steps.
Parent application Ser. Nos. 07/464,511 (now U.S. Pat. No. 5,095,126) and 07/847,295 (now U.S. Pat. No. 5,298,526) relate to the preparation of optically pure stereogenically labile 4-substituted-2-hydroxytetronic acid compounds.